rs751410815

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PP3_ModerateBP6

The NM_000136.3(FANCC):c.668T>C(p.Val223Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,607,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V223V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 1 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 5.32

Publications

2 publications found

Variant links:

Genes affected

FANCC (HGNC:3584): (FA complementation group C) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]

FANCC links:

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

AOPEP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.911

BP6

Variant 9-95149941-A-G is Benign according to our data. Variant chr9-95149941-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216290.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000136.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCC	NM_000136.3	MANE Select	c.668T>C	p.Val223Ala	missense	Exon 7 of 15	NP_000127.2	Q00597
FANCC	NM_001243743.2		c.668T>C	p.Val223Ala	missense	Exon 7 of 15	NP_001230672.1	A0A024R9N2
FANCC	NM_001243744.2		c.668T>C	p.Val223Ala	missense	Exon 7 of 14	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCC	ENST00000289081.8	TSL:1 MANE Select	c.668T>C	p.Val223Ala	missense	Exon 7 of 15	ENSP00000289081.3	Q00597
FANCC	ENST00000375305.6	TSL:1	c.668T>C	p.Val223Ala	missense	Exon 7 of 15	ENSP00000364454.1	Q00597
FANCC	ENST00000490972.7	TSL:1	c.668T>C	p.Val223Ala	missense	Exon 7 of 14	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000873

AC:

AN:

240574

AF XY:

0.0000540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000541

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000184

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1455500

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

723174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.000551

AC:

AN:

43550

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25916

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.00

AC:

AN:

84822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1109092

Other (OTH)

AF:

0.0000166

AC:

AN:

60236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia (2)

Fanconi anemia complementation group C (2)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.3

PhyloP100

5.3

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.46

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.046

Polyphen

0.99

Vest4

0.83

MutPred

0.85

Gain of disorder (P = 0.1877)

MVP

0.87

MPC

0.32

ClinPred

0.74

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.33

gMVP

0.46

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over